Browsing by Subject "cytotoxicity"

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  • Bimbo, Luis M.; Sarparanta, Mirkka; Santos, Helder A.; Airaksinen, Anu J.; Makila, Ermei; Laaksonen, Timo; Peltonen, Leena; Lehto, Vesa-Pekka; Hirvonen, Jouni; Salonen, Jarno (AMERICAN CHEMICAL SOCIETY., 2010)
  • Bimbo, Luis M.; Sarparanta, Mirkka; Santos, Helder A.; Airaksinen, Anu J.; Makila, Ermei; Laaksonen, Timo; Peltonen, Leena; Lehto, Vesa-Pekka; Hirvonen, Jouni; Salonen, Jarno (AMERICAN CHEMICAL SOCIETY., 2010)
  • Ruokonen, Suvi-Katriina; Sanwald, Corinna; Robciuc, Alexandra; Hietala, Sami; Rantamäki, Antti H.; Witos, Joanna; King, Alistair W. T.; Lämmerhofer, Michael; Wiedmer, Susanne K. (2018)
    This study aims at extending the understanding of the toxicity mechanism of ionic liquids (ILs) using various analytical methods and cytotoxicity assays. The cytotoxicity of eight ILs and one zwitterionic compound was determined using mammalian and bacterial cells. The time dependency of the IL toxicity was assessed using human corneal epithelial cells. Hemolysis was performed using human red blood cells and the results were compared with destabilization data of synthetic liposomes upon addition of ILs. The effect of the ILs on the size and zeta potential of liposomes revealed information on changes in the lipid bilayer. Differential scanning calorimetry was used to study the penetration of the ILs into the lipid bilayer. Pulsed field gradient nuclear magnetic resonance spectroscopy was used to determine whether the ILs occurred as unimers, micelles, or if they were bound to liposomes. The results show that the investigated ILs can be divided into three groups based on the cytotoxicity mechanism: cell wall disrupting ILs, ILs exerting toxicity through both cell wall penetration and metabolic alteration, and ILs affecting solely on cell metabolism.
  • Al-Samadi, Ahmed; Awad, Shady Adnan; Tuomainen, Katja; Zhao, Yue; Salem, Abdelhakim; Parikka, Mataleena; Salo, Tuula (2017)
    The crosstalk between immune cells, cancer cells, and extracellular vesicles (EVs) secreted by cancer cells remains poorly understood. We created three-dimensional (3D) cell culture models using human leiomyoma discs and Myogel to study the effects of immune cells on highly (HSC-3) and less (SCC-25) invasive oral tongue squamous cell carcinoma (OTSCC) cell lines. Additionally, we studied the effects of EVs isolated from these cell lines on the cytotoxicity of CD8(+) T and NK cells isolated from three healthy donors. Our analysis included the effects of these EVs on innate immunity in zebrafish larvae. Activated immune cells significantly decreased the proliferation of both OTSCC cell lines and associated with a diminished invasion area of HSC-3 cells. In general, EVs from SCC-25 increased the cytotoxic activity of CD8(+) T and NK cells more than those from HSC-3 cells. However, this effect varied depending on the source and the immune and cancer cell subgroups. In zebrafish, the amount of IL-13 mRNA was decreased by SCC-25 EVs. This study describes promising in vitro and in vivo models to investigate interactions between immune cells, cancer cells, and EVs.
  • Räisänen, Riikka; Primetta, Anja; Nikunen, Sari; Honkalampi, Ulla; Nygren, Heli; Pihlava, Juha-Matti; Vanden Berghe, Ina; von Wright, Atte (2020)
    Biocolourants have been investigated as alternatives to synthetic dyes. However, natural origin per se is not a label of harmlessness and research is needed to obtain safe dyes. We studied the cytotoxicity of the extracts from fungal (Cortinarius semisanguineus, Tapinella atrotomentosa) and plant (Tanacetum vulgare, Salix phylicifolia) sources and the woollen fabrics dyed with the extracts. Cytotoxicity in vitro using hepa-1 mouse hepatoma cells for 24 h and 72 h exposure was observed as the highest tolerated dose. All biocolourants produced intensive colour on fabrics with fastness properties from moderate to good. The Salix and Cortinarius samples did not show any cytotoxic effects, whereas the Tanacetum and Tapinella samples had slightly higher test values but were not interpreted as being significantly toxic. Higher than zero values of the undyed fabrics showed the importance of examining their toxicity as well. It was found that the cytotoxicity of the samples dyed with the biocolourants did not differ significantly from the undyed wool fabric. The concentrations of dyes used in the assays were very low, imitating the dose of the user. In addition to colouring properties, natural dyes may have pharmaceutical and antibacterial properties which would enhance the interest in using them in products for added value.
  • Sokka, Iris Katariina; Ekholm, Filip S.; Johansson, Mikael P. (2019)
    Monomethyl auristatin E and monomethyl auristatin F are widely used cytotoxic agents in antibody-drug conjugates (ADCs), a group of promising cancer drugs. The ADCs specifically target cancer cells, releasing the auristatins inside, which results in the prevention of mitosis. The auristatins suffer from a potentially serious flaw, however. In solution, the molecules exist in an equal mixture of two conformers, cis and trans. Only the trans-isomer is biologically active and the isomerization process, i.e., the conversion of cis to trans is slow. This significantly diminishes the efficiency of the drugs and their corresponding ADCs, and perhaps more importantly, raises concerns over drug safety. The potency of the auristatins would be enhanced by decreasing the amount of the biologically inactive isomer, either by stabilizing the transisomer or destabilizing the cis-isomer. Here, we follow the computer-aided design strategy of shifting the conformational equilibrium and employ high-level quantum chemical modeling to identify promising candidates for improved auristatins. Coupled cluster calculations predict that a simple halogenation in the norephedrine/phenylalanine residues shifts the isomer equilibrium almost completely toward the active trans-conformation, due to enhanced intramolecular interactions specific to the active isomer.
  • Bruun, Tanja (Helsingfors universitet, 2018)
    Marine organisms can be regarded as a diverse source of bioactive compounds with the possibility to discover novel drug lead molecules. Sea sponges produce bromine containing alkaloids, bromotyrosines, from which several are active against cancer. Some bromotyrosines have spirocyclic structure and the innate three-dimensionality and structural novelty of spirocycles make them an interesting option in drug design. Clavatadine C, extracted from sponge Suberea clavata, is a bromine containing spirocyclohexa-dienylisoxazoline alkaloid. It’s symmetric spirocyclic core can be viewed as a restricted derivative of open chain oximes, such as purpurealidin I, a bromotyrosine extracted from Pseudoceratina purpurea. Earlier work with purpurealidin I derivatives against melanoma cell line has had some promising results. Inspired by these earlier results, eight spirocyclic clavatadine C derivatives were synthesized according the published synthesis route. The activities of seven synthesized clavatadine C derivatives were tested on A375 melanoma cell line. All spiro derivatives were active with CC50 values ranging between 1.0 μM and 3.4 μM. Also, the activities of 10 earlier synthesized bromotyrosine derivatives were tested, from which four open chain oximes had CC50 values between 13.5 μM and 27.8 μM. Interestingly, the most active compounds were chlorinated and unhalogenated spirocyclic derivatives. In general, the spirocyclic compounds were 2- to 8-fold more active than the corresponding open chain oximes. The selectivity of active compounds was determined as cytotoxicity against Hs27 fibroblasts and by comparing the CC50 values of these two cell lines. The most selective compound was brominated derivative which had three times better selectivity against melanoma cells. The weak selectivity was consistent with the trend with open chain oxime analogs. Despite the selectivity issue, the improved activity of spirocyclic derivatives are promising and support for further investigation of marine-based spirocyclic bromotyrosine derivatives against melanoma.
  • Fallarero, Adyary; Batista-González, Ana; Hiltunen, Anna K.; Liimatainen, Jaana; Karonen, Maarit; Vuorela, Pia M. (2015)
    Natural products are complex matrices of compounds that are prone to interfere with the label-dependent methods that are typically used for cytotoxicity screenings. Here, we developed a label-free Electric Cell-substrate Impedance Sensing (ECIS)-based cytotoxicity assay that can be applied in the assessment of the cytotoxicity of natural extracts. The conditions to measure the impedance using ECIS were first optimized in mice immortalized hypothalamic neurons GT1-7 cells. The performance of four natural extracts when tested using three conventional cytotoxicity assays in GT1-7 cells, was studied. Betula pendula (silver birch tree) was found to interfere with all of the cytotoxicity assays in which labels were applied. The silver birch extract was also proven to be cytotoxic and, thus, served as a proof-of-concept for the use of ECIS. The extract was fractionated and the ECIS method permitted the distinction of specific kinetic patterns of cytotoxicity on the fractions as well as the extract's pure constituents. This study offers evidence that ECIS is an excellent tool for real-time monitoring of the cytotoxicity of complex extracts that are difficult to work with using conventional (label-based) assays. Altogether, it offers a very suitable cytotoxicity-screening assay making the work with natural products less challenging within the drug discovery workflow.
  • Zahoranova, Anna; Luxenhofer, Robert (2021)
    For many decades, poly(2-oxazoline)s and poly(2-oxazine)s, two closely related families of polymers, have led the life of a rather obscure research topic with only a few research groups world-wide working with them. This has changed in the last five to ten years, presumably triggered significantly by very promising clinical trials of the first poly(2-oxazoline)-based drug conjugate. The huge chemical and structural toolbox poly(2-oxazoline)s and poly(2-oxazine)s has been extended very significantly in the last few years, but their potential still remains largely untapped. Here, specifically, the developments in macromolecular self-assemblies and non-covalent drug delivery systems such as polyplexes and drug nanoformulations based on poly(2-oxazoline)s and poly(2-oxazine)s are reviewed. This highly dynamic field benefits particularly from the extensive synthetic toolbox poly(2-oxazoline)s and poly(2-oxazine)s offer and also may have the largest potential for a further development. It is expected that the research dynamics will remain high in the next few years, particularly as more about the safety and therapeutic potential of poly(2-oxazoline)s and poly(2-oxazine)s is learned.
  • Patel, Piyush A.; Bruun, Tanja; Ilina, Polina; Mäkkylä, Heidi; Lempinen, Antti; Yli-Kauhaluoma, Jari; Tammela, Päivi; Kiuru, Paula (2021)
    Marine-originated spirocyclic bromotyrosines are considered as promising scaffolds for new anticancer drugs. In a continuation of our research to develop potent and more selective anticancer compounds, we synthesized a library of 32 spirocyclic clavatadine analogs by replacing the agmatine, i.e., 4-(aminobutyl)guanidine, side chain with different substituents. These compounds were tested for cytotoxicity against skin cancer using the human melanoma cell line (A-375) and normal human skin fibroblast cell line (Hs27). The highest cytotoxicity against the A-375 cell line was observed for dichloro compound 18 (CC50 0.4 +/- 0.3 mu M, selectivity index (SI) 2). The variation of selectivity ranged from SI 0.4 to reach 2.4 for the pyridin-2-yl derivative 29 and hydrazide analog of 2-picoline 37. The structure-activity relationships of the compounds in respect to cytotoxicity and selectivity toward cancer cell lines are discussed.
  • Imlimthan, Surachet; Correia, Alexandra; Figueiredo, Patricia Isabel; Lintinen, Kalle; Balasubramanian, Vimalkumar; Airaksinen, Anu; Kostiainen, Mauri A.; Almeida Santos, Helder; Sarparanta, Mirkka Päivikki (2020)
    Natural biopolymer nanoparticles (NPs), including nanocrystalline cellulose (CNC) and lignin, have shown potential as scaffolds for targeted drug delivery systems due to their wide availability, cost‐efficient preparation, and anticipated biocompatibility. Since both CNC and lignin can potentially cause complications in cell viability assays due to their ability to scatter the emitted light and absorb the assay reagents, we investigated the response of bioluminescent (CellTiter‐Glo®), colorimetric (MTT® and AlamarBlue®) and fluorometric (LIVE/DEAD®) assays for the determination of the biocompatibility of the multimodal CNC and lignin constructs in murine RAW 264.7 macrophages and 4T1 breast adenocarcinoma cell lines. Here, we have developed multimodal CNC and lignin NPs harboring the radiometal chelator DOTA (1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid) and the fluorescent dye Cyanine 5 for the investigation of nanomaterial biodistribution in vivo with nuclear and optical imaging, which were then used as the model CNC and lignin nanosystems in the cell viability assay comparison. CellTiter‐Glo® based on the detection of ATP‐dependent luminescence in viable cells revealed to be the best assay for both nanoconstructs for its robust linear response to increasing NP concentration and lack of interference from either of the NP types. Both multimodal CNC and lignin NPs displayed low cytotoxicity and favorable interactions with the cell lines, suggesting that they are good candidates for nanosystem development for targeted drug delivery in breast cancer and for theranostic applications. Our results provide useful guidance for cell viability assay compatibility for CNC and lignin NPs and facilitate the future translation of the materials for in vivo applications.
  • Tilli, Irene (Helsingfors universitet, 2017)
    Melanoma is the most severe case of skin cancer and there is no curative treatment if it has progressed. Despite the recent advances in drug therapy tens of thousands of patients die of melanoma annually. There is still need for new antimelanoma drugs for which marine compounds are a potential source. Halogens are common elements in drug molecules as they enhance their molecular properties. So far most of the halogenated drugs contain fluorine and/or chlorine but the role of bromine and iodine is probably growing in the future due to halogen bonding. Bromotyrosines are originally isolated from Verongiida-order sponges but whether they are truly of bacterial origin is under controversy. All bromotyrosine compounds consist of brominated tyrosine and/or tyramine residues or their derivatives. Purpurealidin I is one of the newest bromotyrosine derivatives extracted from Pseudoceratina purpurea and it has shown activity against melanoma. In this study eight new purpurealidin I derivatives were synthesized following a successful route previously designed. All synthesized derivatives contained the original N-oxime structure which's stereochemistry was determined to be E by X-ray crystallography. Cytotoxicity against A375 melanoma cells was determined for seven compounds synthesized here and for 15 compounds synthesized previously. All seven compounds and one previously synthesized purpurealidin I analog were active with CC50 values between 4,7 and 22,1 µM. The previously synthesized bromotyrosine derivative intermediates and aerophobin-1 analogs were not active. The selectivity of the active compounds was calculated by determining their CC50 value against Hs27 fibroblast cells. None of the compounds showed remarkable selectivity the most selective 2-pyridin containing derivative having four times better selectivity against melanoma. The tyrosine part and N-oxime seem to be important parts to preserve while the tyramine part can be modified more freely and maintain the activity. Still more derivatives need to be synthesized and tested to confirm these observations. More data is also needed considering the selectivity of the compounds.